Firing clamp: a novel method for single-trial estimation of excitatory and inhibitory synaptic neuronal conductances

Abstract

Understanding non-stationary neuronal activity as seen in vivo requires estimation of both excitatory and inhibitory synaptic conductances from a single trial of recording. For this purpose, we propose a new intracellular recording method, called “firing clamp.” Synaptic conductances are estimated from the characteristics of artificially evoked probe spikes, namely the spike amplitude and the mean subthreshold potential, which are sensitive to both excitatory and inhibitory synaptic input signals. The probe spikes, timed at a fixed rate, are evoked in the dynamic-clamp mode by injected meander-like current steps, with the step duration depending on neuronal membrane voltage. We test the method with perforated-patch recordings from isolated cells stimulated by external application or synaptic release of transmitter, and validate the method with simulations of a biophysically-detailed neuron model. The results are compared with the conductance estimates based on conventional current-clamp recordings.

Synaptic Conductances during Interictal Discharges in Pyramidal Neurons of Rat Entorhinal Cortex

“…Algebraic calculations provide estimates for the corresponding conductances if the averaged synaptic responses are recorded at two or more different membrane potentials. In spite of its common use in in vivo and in vitro studies, this method cannot be extended to measure three or more conductances while assuming the linear-voltage dependence of the synaptic currents, because under such conditions, only two input variables control a neuron (Pokrovskii, 1978 ; Odom and Borisyuk, 2012 ; Chizhov et al, 2014 ). In the present study, we estimated three conductances by exploring the non-linearity of NMDAR-mediated current and using direct measurements of current-voltage dependences for each synaptic component and its reversal potential.…”

“…In fact, the voltage-dependence of NMDAR-mediated conductance has an amplifying effect that exposes negative conductance (Smirnova et al, 2015 ), similar to the effect of persistent sodium channels, which is explained in detail by Vervaeke et al ( 2006 ). This effect might be unavoidable in single-trial conductance estimates (Chizhov et al, 2014 ).…”

Estimation of Synaptic Activity during Neuronal Oscillations

“…Estimations of the time course of synaptic conductances arriving at a single cell (or a population) reveal relevant information to fully understand the functional connectivity of the brain. Several strategies have been developed for the estimation during subthreshold activity regimes [3][4][5][6][7][8][9][10][12][13][14][15][16][17][18][19][21][22][23]25]. However, the estimation during oscillatory (spiking) regimes has received less attention [25][26][27]40].…”

“…Several strategies have been developed for the estimation during subthreshold activity regimes [3][4][5][6][7][8][9][10][12][13][14][15][16][17][18][19][21][22][23]25]. However, the estimation during oscillatory (spiking) regimes has received less attention [25][26][27]40]. The main drawback is the predominance of ionic currents over synaptic ones in this regime.…”

“…On the other hand, a line of research is devoted to look for possible strategies to estimate conductances in the spiking regime. For instance, in [25], the authors use a firing clamp technique where a description of the spike is given in terms of the membrane potential threshold and the amplitude of the spike. These traces are approximated by calibrating the membrane potential using dynamic clamp in in vitro experiments of isolated neurons and a quadratic polynomial approximation.…”